Mutation screening of the Wolfram syndrome gene in psychiatric patients

Wolfram syndrome, a rare autosomal recessive neurodegenerative disorder, was originally described as a combination of familial juvenile-onset diabetes mellitus and optic atrophy. It was later demonstrated that Wolfram syndrome patients were highly prone to psychiatric disorders. Mutations in exon 8 of the Wolfram syndrome gene account for 88% of the patients with Wolfram syndrome. To examine whether the gene responsible for causing Wolfram syndrome is involved in psychiatric disorders, we screened exon 8 of the Wolfram syndrome gene for mutations in 119 patients with schizophrenia, one patient with schizoaffective disorder, 12 patients with bipolar disorder and 15 patients with major depression, using sequence analysis. In Wolfram syndrome patients, this gene has been shown to have primarily nonsense or frameshift mutations, which would result in a premature truncation of the protein. None of the psychiatric patients screened in this study carried these types of mutations. We identified, however, 24 new variations whose significance remains to be determined.     

Chronic ataxic neuropathy initially diagnosed as ataxic variant of guillain barré syndrome

Aquadynia is a rare phenomenon of water‐induced pain through presumed neural mechanisms. We describe two women in whom bathing was regularly followed by pain in the lower limbs, as a unique symptom (case 1) and, respectively, in the clinical context of an axonal polyneuropathy (case 2). Case 1: A 71‐year‐old woman complained, by age 69, of pruritus and pinprick‐like pain in the extremities that lasted about 20 minutes following bathing. Neurological examination and electroneurography were negative, as well as investigations for systemic diseases. Quantitative sensory testing (QST) showed abnormal cold‐pain sensation. Treatment with gabapentin was not effective. Case 2: A 69‐year‐old woman affected with HCV‐related cryoglobulinemia had numbness and aquadynia in the distal lower limbs and restless legs syndrome, in the last few months. Neurological examination showed absent ankle jerks, and decreased touch and vibration sense in the feet. Electroneurography demonstrated an axonal neuropathy. Aquadynia likely represents a manifestation of small fiber neuropathy. It is unclear whether it has to be viewed as a primary sensory phenomenon similar to allodynia, or a type of noradrenergic pain primarily due to autonomic dysfunction. Alteration of QST in case 1, and the association with obvious features of sensory neuropathy in case 2, may favour the sensory hypothesis.     

Wolfram syndrome: a clinicopathologic correlation

Wolfram syndrome or DIDMOAD (diabetes insipidus, diabetes mellitus, optic atrophy and deafness) is a neurodegenerative disorder characterized by diabetes mellitus and optic atrophy as well as diabetes insipidus and deafness in many cases. We report the post-mortem neuropathologic findings of a patient with Wolfram syndrome and correlate them with his clinical presentation. In the hypothalamus, neurons in the paraventricular and supraoptic nuclei were markedly decreased and minimal neurohypophyseal tissue remained in the pituitary. The pontine base and inferior olivary nucleus showed gross shrinkage and neuron loss, while the cerebellum was relatively unaffected. The visual system had moderate to marked loss of retinal ganglion neurons, commensurate loss of myelinated axons in the optic nerve, chiasm and tract, and neuron loss in the lateral geniculate nucleus but preservation of the primary visual cortex. The patient’s inner ear showed loss of the organ of Corti in the basal turn of the cochleae and mild focal atrophy of the stria vascularis. These findings correlated well with the patient’s high-frequency hearing loss. The pathologic findings correlated closely with the patient’s clinical symptoms and further support the concept of Wolfram syndrome as a neurodegenerative disorder. Our findings extend prior neuropathologic reports of Wolfram syndrome by providing contributions to our understanding of eye, inner ear and olivopontine pathology in this disease.     

Chronic ataxic neuropathy mimicking dorsal midbrain syndrome

We describe the clinical course, with special attention to the disturbance of eye movements, of a 29-year-old man with chronic ataxic neuropathy with ophthalmoplegia, IgM paraprotein, cold agglutinins and anti-GD1b disialosyl antibodies (CANOMAD). Using the magnetic search coil technique, we documented convergence during upward saccades and other features suggestive of dorsal midbrain syndrome. Thus, in common with Miller Fisher syndrome, CANOMAD may present with clinical findings implicating involvement of the central nervous system, which contains ganglioside antigens to anti-GD1b antibodies.     

Wolfram syndrome: a neuropathological study

Neuropathological examination was carried out on a patient aged 37 years who had suffered from Wolfram syndrome. Atrophy of the olfactory bulbs and tracts, atrophy of the optic nerves and chiasm, loss of neurons in the lateral geniculate nuclei mainly affecting the small cell layers, atrophy of the superior colliculus, loss of fibers in the cochlear nerve and mild loss of neurons in the cochlear nuclei and inferior colliculus, mild olivopontocerebellar atrophy, and demyelination of the pyramidal tracts were the main neuropathological findings. These correlated with anosmia, loss of vision, loss of hearing, cerebellar symptoms and signs, Babinski sign, and clonus, respectively, clinically observed in this patient. Mild neuron loss and gliosis in the preoptic and paraventricular area of the hypothalamus and mild motor neuron loss in the spinal cord did not reach thresholds of impaired function, although loss of neurons in discrete bulbar nuclei might have accounted for the late episode of food aspiration and suffocation. The relationship between memory loss, personality disturbances, and signs of prefrontal release and mild loss of neurons in the anterior and dorsomedial nuclei of the thalamus remains unclear. Received: 30 August 1996 / Revised, accepted: 31 October 1996     

Evidence of widespread axonal pathology in Wolfram syndrome

Wolfram syndrome, characterised by diabetes insipidus, diabetes mellitus, optic atrophy sensorineural deafness and acquired urinary tract abnormalities, is an hereditary neurodegenerative syndrome, the pathogenesis of which is unknown. We report the post-mortem findings on a patient with well-documented Wolfram syndrome. The brain showed severe degeneration of the optic nerves, chiasm and tracts as well as severe loss of neurons from the lateral geniculate nuclei, basis pontis, and the hypothalamic paraventricular and supraoptic nuclei. In addition, there was a widespread axonal dystrophy with axonal swellings in the pontocerebellar tracts, the optic radiations, the hippocampal fornices and the deep cerebral white matter. This widespread axonal pathology parallels the pattern of neurodegeneration and in many areas is more striking than neuronal loss. Received: 18 November 1998 / Revised, accepted: 3 February 1999     

A case of Wolfram syndrome: Neurological features

The case of a 24-year-old man with diabetes mellitus, diabetes insipidus, multisensory deficits and peripheral neuropathy is discussed.

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Sommario Trattasi di un caso di un giovane di 24 anni affetto da diabete mellito, diabete insipido, difetti multisensoriali e da neuropatie periferiche.

     

Pontine infarction producing dysarthria-clumsy hand syndrome and ataxic hemiparesis

We describe two patients, one with clumsy hand-dysarthria syndrome and one with ataxic hemiparesis. Both had pontine lesions on CT. Similar clinical syndromes may be seen with lesions of the internal capsule, and it is not possible to predict the lesion's location from clinical information alone. The clinical picture of dysarthria-clumsy hand syndrome or ataxic hemiparesis is also not specific for lacunar infarction.     

Psychiatric disorders in 36 families with Wolfram syndrome

OBJECTIVE: The purpose of this study was to test the hypothesis that heterozygous carriers of the gene for the Wolfram syndrome, who constitute about 1% of the population, are predisposed to significant psychiatric illness. The Wolfram syndrome is an autosomal recessive neurodegenerative syndrome in which 25% of the individuals who are homozygous for the condition have severe psychiatric symptoms that lead to suicide attempts or psychiatric hospitalizations. METHOD: The authors collected questionnaires, death certificates, and hospital records for blood relatives and their spouses in 36 families of individuals with the Wolfram syndrome and compared the proportion of blood relatives who had had psychiatric hospitalizations, had committed suicide, or had self-reported mental illness to the proportion of spouses with the same manifestations. RESULTS: The proportion of blood relatives who had had psychiatric hospitalizations, had committed suicide, or had self-reported mental illness significantly exceeded the proportion of spouses with the same manifestations. CONCLUSIONS: Since heterozygous carriers of the gene for the Wolfram syndrome are 50-fold more common among the blood relatives than among the spouses, the larger proportion among blood relatives is evidence that heterozygous carriers of the gene for the Wolfram syndrome are predisposed to significant psychiatric illness.     

Airflow tracking in patients with ataxic disorders

Expiratory airflow control was examined by tracking tasks in 17 patients with cerebellar disorders and in 25 normal controls. Airflow rate was recorded by an aerometer and fed back visually on the computer screen. Tracking skills were assessed after training based on a ramp-and-hold tracking task. In addition, transfer of skills to a constant tracking task was assessed. The patients showed remarkable tracking deficits relative to the control subjects. The degree of their tracking impairment was less related to perceptual and acoustic measures of dysarthria than to clinical ataxia scores based on limb examinations. The patients were unable to improve their tracking skills over repetitive trials. Yet there was a significant training-related gain in the initiation of tracking tasks, which points to a specific impairment of the tracking process itself in cerebellar ataxia.     

Psychiatric disorders and mutations at the Wolfram syndrome locus.

Identifying genetic loci at which mutations predispose individuals to common psychiatric illnesses will have major impact on the diagnosis and treatment of mental illness. The available evidence indicates that mutations at the Wolfram syndrome locus contribute substantially to the prevalence of psychiatric illness in the general population. Patients with mutations at this locus on both parental chromosomes, called Wolfram syndrome homozygotes, have a distinctive and rare autosomal recessive syndrome characterized by juvenile onset diabetes mellitus and bilateral progressive optic atrophy. Diverse and serious psychiatric manifestations frequently have been observed in Wolfram syndrome patients; however, the population burden of mental illness attributable to mutations at this locus is almost entirely from individuals who carry a single mutation, called Wolfram syndrome heterozygotes, who have no distinguishing physical characteristics but constitute approximately 1% of the population. Molecular genotyping of blood relatives of Wolfram syndrome patients has shown that Wolfram syndrome heterozygotes are 26-fold more likely than noncarriers to have a psychiatric hospitalization. Severe depression was the predominant finding in the test group studied. The prediction that approximately 25% of all patients hospitalized for depression are Wolfram syndrome heterozygotes now can be tested by mutation screening of hospitalized patients from the general population. Many other behavioral and cognitive difficulties also have been observed in Wolfram syndrome families. For each specific psychiatric abnormality, a "test group" of blood relatives within Wolfram syndrome families with that abnormality can be formed. By comparing the number of Wolfram syndrome heterozygotes found in each test group by molecular genotyping with the number expected under the null hypothesis, the index-test method can determine which clinical phenotypes result from mutations at the Wolfram syndrome locus. This method can be utilized to identify other loci at which mutations predispose individuals to psychiatric illnesses.     

Biochemical studies in Tanzanian patients with ataxic tropical neuropathy

Data on thiocyanate and vitamin B₁₂ concentrations in plasma from Tanzanian patients with ataxic tropical neuropathy are presented and support the hypothesis that, as in Nigeria, the condition may result from chronic exposure to cyanide or cyanogens from a diet including large amounts of cassava.